Cell cycle and signaling

1. CELL CYCLE AND SIGNALING

2. Contents
› Introduction
› Phases of cell division
› Checkpoints
› Meiosis
› Mitosis
› Checkpoints and cell cycle regulation
› Significance of cell cycle

3. Cell Cycle
The cellular life cycle also called the cell cycle
it includes many processes necessary for successfulself-replication. Beyond
carrying out the tasks of routine metabolism, the cell mustduplicate its
components most importantly, its genome so that it can physically split into two
complete daughter cells. The cell mustalso pass through a series of
checkpoints that ensure conditions are favorablefor division.
Phases of cell division
The cell cycle consists of four distinct phases:
G1 (Gap1) phase
S phase (synthesis
G2 (Gap2) phase (collectively known as interphase)
and M phase (mitosis).
M (mitosis) phase is itself composed of two tightly coupled processes: mitosis
in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis…
in which the cell's cytoplasmdivides in half forming distinct cells. Activation of each phase is
dependent on the proper progression and completion of the previous one.
Cells that have temporarily or reversibly stopped dividing are said to have entered a state of
quiescence called G0 phase…
G0 phase
The G0 phase is a period in the cell cycle in which cells exist in a quiescent state. G0 phase is
viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to
divide, or a distinct quiescent stage that occurs outside of the cell cycle. G0 is sometimes
referred to as a "post-mitotic" state…
G1 phase
The first phase of interphase is G1 phase, from the end of the previous Mitosis phase until the
beginning of DNA replication is called G1 (G indicating gap). It is also called the growth phase.
During this phase the biosynthetic activities of the cell, which had been considerably slowed
down during M phase, resume at a high rate. This phase is marked by synthesis of various
enzymes that are required in S phase, mainly those needed for DNA replication…

4. S phase
Initiation of DNA replication is indication of S phase; when it is complete, all of the
chromosomes have been replicated, at this time each chromosome has two (sister) chromatids.
Thus, during this phase, the amount of DNA in the cell has effectively doubled, though the
ploidy of the cell remains the same. Rates of RNA transcription and protein synthesis are very
low during this phase. An exception to this is production of histone protein, which mostly
occurs during the S phase.
G2 phase
After S phase or replication cell then enters the G2 phase, which lasts until the cell enters
mitosis. Again, significant biosynthesis occurs during this phase, mainly involving the production
of microtubules, which are required during the process of mitosis. Inhibition of protein
synthesis during G2 phase prevents the cell from undergoing mitosis.
Checkout points
In order to move from one phase of its life cycle to the next, a cell must pass through numerous
checkpoints. At each checkpoint, specialized proteins determine whether the necessary
conditions exist. If so, the cell is free to enter the next phase.
Each part of the cell cycle features its own unique checkpoints. For example, during G1, the cell
passes through a critical checkpoint that ensures environmental conditions are favorable for
replication. If conditions are not favorable, the cell may enter a resting state known as G0.
Some cells remain in G0 for the entire lifetime of the organism in which they reside. For
instance, the neurons and skeletal muscle cells of mammals are typically in G0.
› Another important checkpoint takes place later in the cell cycle, just before a cell moves
from G2 to mitosis. Here, a number of proteins scrutinize the cell's DNA, making sure it
is structurally intact and properly replicated. The cell may pause at this point to allow
time for DNA repair, if necessary.
› Yet another critical cell cycle checkpoint takes place mid-mitosis. This check determines
whether the chromosomes in the cell have properly attached to the spindle, or the
network of microtubules that will separate them during cell division. This step decreases
the possibility that the resulting daughter cells will have unbalanced numbers of
chromosomes a condition called aneuploidy
Checkpoints and Cell Cycle Regulation

5. Process of cell cycle must be highly regulated so that each daughter cell contains the
complement of DNA found in parent cell. There are different mechanisms to control the timing
of events in the context of different cell types. Most important discoveries about mechanisms
that control events of cell were elucidated using yeast. Results have shown many important
control genes are present
CDC Genes
Many cell cycle control genes in mammalian cells are also called cell division cycle genes. Much
of the control of the progression through the phases of a cell cycle are exerted at check points.
Two most critical genes that occur near the end of G1 prior to S-phase entry and those near the
end of G2 prior to mitosis.
Cyclin Dependent Kinase
Heart of timing control is the responsibility of a family of protein kinases that are called CDKs.
Oscillating changes in the activity of CDKs leads to oscillating changes in phosphorylation of
various intracellular proteins. After phosphorylation the cyclins CDK complex is fully active.
Which then effect changes in events of cell cycle.
Cyclins
The cyclical activity of each CDK is controlled by a series of proteins, the most important of
which are cyclins. CDK are dependent upon their interaction with the cyclins for activity unless
they are tightly bound CDKs without kinase activity, level of various CDKs remain fairly constant
throughout the cell cycle, their activities changes in concert with the fluctuations of cyclins.
Four different types of Cyclins are there
G1-Cyclins
They are not found in all eukaryotes but those where they are synthesized they promote
passage through a restriction point in late G1 called Start.

6. G1/S-Cyclins
They bind to their cognate CDKs at the end of G1 and it is the interaction that is required to
commit the cell to the process of DNA replication in S-Phase
S-Cyclins
They bind to their CDKs during S-phase and it is the interaction that is required for the initiation
of DNA synthesis.
M-Cyclins
They bind to their cognate CDKs and in so doing promote the events of mitosis.
Interaction of CDKs
CDKs are inactive unless bound to a cyclin, there is more to activation process than just the
interaction of two parts of complex. When cyclins bind to CDKs they alter the conformation of
CDK resulting in exposure of a domain that is site for phosphorylation by another kinase called
CDK activating Kinase. Proteins that bind to and inhibit cyclin-CDK complexes are called CDK
inhibitory proteins. CKI-cyclin kinase inhibitor (Example P21)
Ubiquitin ligase complexes
The cyclical degradation of cyclins is affected through the action of several different ubiquitin
ligase complexes they are two important ubiquitin ligase complexes. One of them which
function to control transit from G1 to S-phase and the other is called anaphase promoting
complex.
Anaphase promoting Complex
› Controls the level of M-phase cyclins as well other regulators of mitosis.
› Controls initiation of sister chromatids separation which begins at metaphase-anaphase
transition.
Meiosis
Meiosis is the form of eukaryotic cell division that produces haploid sex cells or gametes (which
contain a single copy of each chromosome) from diploid cells (which contain two copies of each
chromosome). The process takes the form of one DNA replication followed by two successive
nuclear and cellular divisions (Meiosis I and Meiosis II). As in mitosis, meiosis is preceded by a
process of DNA replication that converts each chromosome into two sister chromatids.

7. Phases of Meiosis
Two successive nuclear divisions occur, Meiosis I (Reduction) and Meiosis II (Division). Meiosis
produces 4 haploid cells. Mitosis produces 2 diploid cells. The old name for meiosis was
reduction/ division. Meiosis I reduces the ploidy level from 2n to n (reduction) while Meiosis II
divides the remaining set of chromosomes in a mitosis-like process (division). Most of the
differences between the processes occur during Meiosis I
Prophase I
Prophase I has a unique event -- the pairing (by an as yet undiscovered mechanism) of
homologous chromosomes. Synapsis is the process of linking of the replicated homologous
chromosomes. The resulting chromosome is termed a tetrad, being composed of two
chromatids from each chromosome, forming a thick (4-strand) structure. Crossing-over may
occur at this point. During crossing-over chromatids break and may be reattached to a different
homologous chromosome. crossing-over between homologous chromosomes produces
chromosomes with new associations of genes and alleles.
Metaphase I
Metaphase I is when tetrads line-up along the equator of the spindle. Spindle fibers attach to
the centromere region of each homologous chromosome pair. Other metaphase events as in
mitosis.
Anaphase I

8. Anaphase I is when the tetrads separate, and are drawn to opposite poles by the spindle fibers.
The centromeres in Anaphase I remain intact.
Telophase I
Telophase I is similar to Telophase of mitosis, except that only one set of (replicated)
chromosomes is in each "cell". Depending on species, new nuclear envelopes may or may not
form. Some animal cells may have division of the centrioles during this phase.
Prophase II
During Prophase II, nuclear envelopes (if they formed during Telophase I) dissolve, and spindle
fibers reform. All else is as in Prophase of mitosis. Indeed, Meiosis II is very similar to mitosis.

9. Metaphase II
Metaphase II is similar to mitosis, with spindles moving chromosomes into equatorial area and
attaching to the opposite sides of the centromeres in the kinetochore region.
Anaphase II
During Anaphase II, the centromeres split and the former chromatids (now chromosomes) are
segregated into opposite sides of the cell.
Telophase II
Telophase II is identical to Telophase of mitosis. Cytokinesis separates the cells.

10. Mitosis
Mitosis is the division of the eukaryote nucleus, which goes on throughout life in all parts of the
body. Organelles can be randomly separated into the daughter cells but chromosomes must be
precisely divided so that each daughter cell gets exactly the same DNA. Every human cell has
the same 46 chromosomes.
Mitosis is usually divided into 4 phases:
Prophase (P)
Metaphase (M)
Anaphase (A)
Telophase (T)
Prophase
Important events:
The chromosomes condense (the proteins attached to the DNA cause the chromosomes to go
from long thin structures to short fat one, which makes them easier to pull apart). The nuclear
envelope disappears (the double membrane that surround the nucleus dissolves into a
collection of small vesicles, freeing the chromosomes to use the whole cell for division). Pair of
centrioles separate and move to opposite ends of the cell (except in plants). The spindle fibers
(microtubules) start to form, growing out of the centrioles towards the chromosomes.

11. Metaphase
Important events:
Chromosomes line up on the equator of the cell. he centrioles are at opposite ends and the
spindle fibers attach to the centromeres.
Anaphase
Important events:
The centromeres divide (each 2-chromatid chromosome becomes two 1-chromatid
chromosomes). Spindle fibers contract, and the chromosomes are pulled apart to opposite
poles of the cell, towards the centrioles.
Telophase
Important events
chromosomes are at the poles of the cell. spindle fibers and aster disintegrate. nuclear
envelope re-forms around the two sets of chromosomes. cytoplasm is divided into 2 separate
cells = cytokinesis.

12. Cytokinesis
The organelles get divided up into the 2 daughter cells passively: they go with whichever cell
they find themselves in.
Plant x Animal cells:
Plants: a new cell wall made of cellulose forms between the 2 new nuclei (cell plate)
Animals: a ring of actin fibers (microfilaments) forms around the cell equator, pinching the cell
in half.
SIGNIFICANCE OF MITOSIS
In mitosis the hereditary material is equally distributed in the daughter cells; as there is no
crossing over or recombination, the genetic information remains unchanged generation after
generation, thus continuity of similar information is ensured from parent to daughter cells.
Development and growth of multicellular organisms depends upon orderly controlled mitosis.
Regeneration, healing of wounds and replacement of older cells all are the gifts of mitosis.
Tissue culture and cloning seek help through mitosis. For all this organism requires, managed,
controlled, and properly organized process of mitosis if not so it will result in malfunction,
unwanted tumors and lethal diseases like cancers.
Multicellular plants and animals start life as single cells, the zygotes or fertilized egg cells; the
process of Mitosis gives rise to many cells which differentiate to form tissues, organs and
organ-systems of the organism.
Mitosis results in an increase in size and growth of an organism.
It is an equal division through which identical daughter cells are produced having the same
amount and type of genetic constitution as that of the parent cell.
It is responsible for growth and development of multi-cellular organisms from a single-celled
zygote.
The number of chromosomes remains the same in all the cells produced by this division. Thus,
the daughter cells retain the same characters as those of the parent cell.
It helps the cell in maintaining proper size.
Mitosis helps in restoring wear and tear in body tissues, replacement of damaged or lost part,
healing of wounds and regeneration of detached parts (as in tail of lizards).
If mitosis remains unchecked, it may result in uncontrolled growth of cells leading to cancer or
tumor.

13. ERRORS IN MITOSIS
Although errors in mitosis are rare, the process may go wrong, especially during early cellular
divisions in the zygote. Mitotic errors can be especially dangerous to the organism because
future offspring from this parent cell will carry the same disorder.
Deletion: Sometimes during mitosis the chromosomes can be damaged. If the chromosome
gets broken the fragments can be lost. If this happens the genetic material, they contain is
deleted.
Translocation: If the chromosome breaks, it can reattach. Sometimes it reattaches to the wrong
chromosome. This is called translocation
Inversion: When the fragment gets reattached it gets attached to the right chromosome but
upside down. When this happen it incorrect codes for information.
Non-Disjunction: When the sisters fail to separate. One cell is given three copies (trisomy) of a
chromosome while the other gets only one (monosomy). These cells are called Aneuploidic, and
they can cause cancer. A nondisjunction at anaphase I will result in two gametes with a diploid
number for the altered chromosome and two gametes with the chromosome missing
altogether then at anaphase II it will result in two normal gametes, one gamete with two copies
of the chromosome, and one gamete with no copies of the chromosome. The abnormal
gametes are called aneuploid; they have an excess or lack of one or more chromosomes or
pieces of chromosomes.
CONSEQUENCES OF MITOTIC ERRORS
Patau Syndrome results froma trisomy of chromosome 13. One in every 5000 new borns will
inherit this disease characterized by harelip, cleft palate, severe defects to the eyes, brain, and
circulatory system. Most affected newborns die within a year.
Cri-du-chat Syndrome is caused by a specific deletion in chromosome 5. It results in severe
mental retardation, abnormal facial features, a small head, and an abnormally developed larynx
which causes the child's cry to sound like that of a cat. Affected individuals rarely survive past
early childhood.
Edward's Syndrome results froma trisomy of chromosome 18. It affects one in every 10,000
new burn, causing problems for almost every organ system. Most infants with the syndrome
survive less than a year.
Turner syndrome results when females are born with only one X chromosome. These females
are infertile. Turner syndrome usually does not affect intelligence. Common physical symptoms
of Turner Syndrome include a stocky build, arms that turn out slightly at the elbow, a receding
lower jaw, a short webbed neck, and a low hairline at the back of the neck.

14. Klinefelter syndrome occurs in men with an extra X chromosome. Except for small testes, they
have normal sex organs. However, they are sterile, and develop feminine body characteristics.
They usually have normal intelligence. Less common is the occurrence of more than one extra X
chromosomes. Males may have XXY, XXXY, XXXXY, even XXXXXY. These individuals have a
higher incidence of mental retardation than XXY individuals.
Down syndrome results when the nucleus of each cell contains 23 pairs of chromosomes, half
of which are inherited from each parent As a result, some of the body's cells have the usual two
copies of chromosome 21, and other cells have three copies of this chromosome. Down
syndrome occurs when an individual has a full or partial extra copy of chromosome 21. The
condition leads to impairments in both cognitive ability and physical growth that range from
mild to moderate developmental disabilities.
Cancer (uncontrolled cell division), Mitosis is closely controlled by the genes inside every cell.
Sometimes this control can go wrong. If that happens in just a single cell, it can replicate itself
to make new cells that are also out of control. These are cancer cells. They continue to replicate
rapidly without the control systems that normal cells have. Cancer cells will form lumps, or
tumors, that damage the surrounding tissues. Sometimes, cancer cells break off from the
original tumors and spread in the blood to other parts of the body. When a tumor spreads to
another part of the body it is said to have metastasized. They continue to replicate and make
more tumors. These are called secondary tumors.
SIGNIFICANCE OF MEIOSIS
Crossing over and random assortment of chromosomes are two significant happenings of
meiosis. During crossing over, parental chromosomes exchange segments with each other
which results in a large number of recombination’s. At the same time during anaphase the
separation of homologous chromosomes is random, which gives wide range of variety of
gametes both of these causing variations and modifications in the genome. Meiosis allows for
new combination of genes to occur in the gametes (cells involved in sexual reproduction). This
leads to genetic variation in the offspring. Meiosis is for the health and it increases genetic
diversity, continue evolution, and maintain a species.
CONSEQUENCES OF MEIOSIS
Errors that may occur during meiosis include the incorrect copying of the DNA sequence when
the DNA is replicated before division, errors during recombination or errors when the
chromosomes segregate to the daughter cells.
I.Too Many or Too Few Chromosomes: Sometimes chromosomes are incorrectly distributed
into the egg or sperm cells during meiosis. When this happens, one cell may get two copies of a
chromosome, while another cell gets none. Disease resulting from too many or too few
chromosomes includes:

15. Klinefelter Syndrome (XXY)
Turner Syndrome (X)
Down Syndrome (Trisomy 21)
II. Missing pieces: Sometimes pieces of chromosomes are lost or rearranged during meiosis.
When genetic material is missing, a chromosome is said to have a deletion. Deletions of the tips
of chromosomes are called terminal deletions. Internal deletions, where a chromosome has
broken, lost material, and rejoined, are called interstitial deletions. Diseases resulting from
chromosome deletions include:
Cri-du-Chat Syndrome (Chromosome 5)
Williams Syndrome (Chromosome 7)